This invention is directed to compounds of the formula I as described herein, to a pharmaceutical composition comprising such compounds and to methods of treating disorders or conditions that may be treated by administration of such compounds to a mammal in need, including humans. In particular, the compounds of the current invention are potentially useful for treating stroke, Huntington's disease and amyotrophic lateral sclerosis (ALS).
Neurodegeneration refers to the progressive loss of structure or function, including death, of neurons. Neurodegenerative diseases include ALS (amyotrophic lateral sclerosis), Parkinson's, Alzheimer's, and Huntington's diseases and occur as a result of neurodegenerative processes. They are incurable, resulting in progressive degeneration and/or death of neuron cells.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease and Charcot disease, is a specific disorder that involves the death of neurons. ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscle wasting. This results in difficulty speaking, swallowing, and eventually impairs breathing.
ALS is classified as a rare disease, but is the most common motor neuron disease. People of all races and ethnic backgrounds are affected. The cause is not known in 90% to 95% of cases. About 5-10% of cases are inherited from a person's parents. About half of these genetic cases are due to one of two specific genes. It results in the death of the neurons that control voluntary muscles. The diagnosis is based on a person's signs and symptoms with testing done to rule out other potential causes.
There is no cure for ALS. A medication called riluzole may extend life expectancy by about two to three months. Non-invasive ventilation may result in both improved quality and length of life. The disease usually starts around the age of 60 and in inherited cases around the age of 50. The average survival from onset to death is three to four years. About 10% survive longer than 10 years. Most die from respiratory failure. In much of the world, rates of ALS are unknown. In Europe, the disease affects about 2.2 people per 100,000 per year. In the United States, more than 5,600 are diagnosed every year, and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 people per year.
Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to mental decline and behavioral symptoms. Symptoms of the disease can vary between individuals and affected members of the same family, but usually progress predictably. The earliest symptoms are often subtle problems with mood or cognition. A general lack of coordination and an unsteady gait often follows. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral symptoms. Physical abilities gradually worsen until coordinated movement becomes difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years from the point at which symptoms begin.
Physical symptoms can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. The disease may develop earlier in life in each successive generation. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid, or Westphal variant HD. The late onset of Huntington's disease means it does not usually affect reproduction.
The worldwide prevalence of HD is 5-10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the U.K. between 1990 and 2010 found that the average prevalence for the U.K. was 12.3 per 100,000.
HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea. The disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin.
There is no cure for HD, and full-time care is required in the later stages of the disease. Existing pharmaceutical and non-drug treatments can relieve many of its symptoms. It is much more common in people of Western European descent than in those of Asian or African ancestry. The disease can affect both men and women.
Tetrabenazine was approved in 2008 for treatment of chorea in Huntington's disease in the US. Other drugs that help to reduce chorea include neuroleptics and benzodiazepines. Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results. Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid.
Stroke, also known as cerebrovascular accident (CVA), cerebrovascular insult (CVI), or brain attack, occurs when poor blood flow to the brain results in cell death. There are two main types of stroke: ischemic due to lack of blood flow and hemorrhagic due to bleeding. They result in part of the brain not functioning properly. Signs and symptoms of a stroke may include an inability to move, problems understanding or speaking, and loss of vision to one side. Signs and symptoms often appear soon after the stroke has occurred. If symptoms last less than one or two hours it is known as a transient ischemic attack (TIA). Hemorrhagic strokes may also be associated with a severe headache. The symptoms of a stroke can be permanent. Long term complications may include pneumonia or loss of bladder control.
Prevention includes decreasing risk factors as well as possibly aspirin, statins, surgery to open up the arteries to the brain in those with problematic narrowing, and warfarin in those with atrial fibrillation. A stroke often requires emergency care. An ischemic stroke, if detected within three to four and half hours, may be treatable with a medication that can break down the clot. Aspirin should be used. Some hemorrhagic strokes benefit from surgery. Treatment to try recover lost function is called rehabilitation and ideally takes place in a stroke unit; however, these are not available in much of the world.
In 2010, approximately 17 million people had a stroke and 33 million people had previously had a stroke and were still alive. Between 1990 and 2010 the number of strokes which occurred each year decreased by approximately 10% in the developed world and increased by 10% in the developing world. In 2013, stroke was the second most frequent cause of death after coronary artery disease, accounting for 6.4 million deaths (12% of the total). About 3.3 million deaths resulted from ischemic stroke while 3.2 million deaths resulted from hemorrhagic stroke. About half of people who have had a stroke live less than one year. Overall, two thirds of strokes occurred in those over 65 years old.
Recently, there has been increased awareness of the potential for compounds which function as sigma-1 receptor ligands. The structure and functions of the “receptor” have been described in a variety of publications (e.g., Duncan G and Wang L (2005) Experimental Eye Research, 81:121-122; Ortega-Roldan J L, Ossa F, Schnell J R (2013) Journal of Biological Chemistry, 288(29):21448-21457; Monnet F P (2005) Biol. Cell 97:873-883 (doi:10.1042/BC20040149); Ishikawa M, Hashimoto K (2010) Journal of Receptor, Ligand and Channel Research, 3:25-36)
In a paper by Nguyen, et al (Nguyen L, Lucke-Wold B P, Mookerjee S A Cavendish J Z, Robson M J, Scandinaro A L and Matsumoto R R, Journal of Pharmacological Sciences (2015) 127:17-29), the mechanisms of neurodegeneration and the potential for the use of highly selective sigma-1 receptor ligands is discussed in great detail. They describe the mechanisms by which drugs that interact with the sigma-1 receptor may confer neuroprotection, including calcium homeostasis, attenuation of reactive species (e.g., NO) production, modulation of endoplasmic reticulum (ER) and mitochondrial function and modulation of glial activity. Because of these capabilities, they postulate that sigma-1 ligands may have beneficial effects in the treatment of stroke, ALS and Huntington's diseases.
In animal studies, rats treated with the sigma-1 agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride within two days of induced ischemic injury showed enhanced recovery of lost sensorimotor function without decreasing infarct size, suggesting that sigma-1 activation stimulates recovery after stroke by stimulating brain plasticity (Ruscher K, Shamloo M, Rickhag M, Ladunga I, Soriano L, et al (2011) Brain; doi:10.1093/brain/awq367). A sigma-1 selective antagonist, BD1063, as well as the potent antipsychotic drug haloperidol (also a potent sigma-1 antagonist) also showed neuroprotective activity at low doses when administered acutely as a protective agent against cerebral ischemic stroke in in vivo animal studies (Schetz J A, Perez E, Liu R, Chen S, Lee I and Simpkins J W (2007) Brain Research, 1181:1-9; doi:10.1016/j.brainres.2007.08.068)
For example, the sigma-1 agonist cutamesine (SA4503) was recently studied in a Phase 2 trial with a group of 60 patients suffering from ischemic stroke (Urfer R, Moebius H J, et al (2014) Stroke, 45:3304-3310). No adverse effects were observed and additional studies were planned.
The present invention relates to the use of novel cycloalkyl-diamines and to their pharmaceutical compositions in the treatment of neurodegenerative disorders from the group consisting of stroke, Huntington's disease and amyotrophic lateral sclerosis (ALS) in mammals, including humans. Many of the compounds disclosed in this application exhibit significant affinity as sigma-1 ligands.